The present invention relates to a drug comprising doxazosin mesylate in crystal modification D.
Doxazosin (=4-amino-2-[4-(1,4-benzodioxan-2-carbonyl)piperazin-1yl-]6,7-dimethoxyquinazoline) is a known substance (Merck Index, 12th edition 1996, No. 3489) which lowers blood pressure. The substance is mainly used in the form of the monomesylate which, in crystalline form, occurs in several modifications. Thus, three crystal modifications which are referred to as modifications A, B and C are described in the Chinese Journal of Medicinal Chemistry 5(4), 266-270 (1995). Modification A is obtained on recrystallization of doxazosin mesylate from ethanol. Modifications B and C result on recrystallization of doxazosin mesylate from chloroform and water respectively. Mention may be made of the fact that the Chinese Journal of Medicinal Chemistry in fact speaks simply of doxazosin. However, according to the published data, the material must be doxazosin mesylate. Modification A is also the subject of EP-A 0 849 266, where it is referred to as form III.
Another modification has been described and characterized in EP-A 0 848 001, but it was not given a special name. EP-A 0 849 264 describes a form I and EP-A 0 849 265 describes a form II of doxazosin mesylate.
The patent application PCT/EP/98/08360 (filed on Dec. 18, 1998), unpublished at the priority date of the present specification, describes a form D of doxazosin mesylate which occurs as intermediate in the preparation of form A of doxazosin mesylate.
It has now been found that modification D of doxazosin mesylate can be used particularly satisfactorily as a drug for high blood pressure.
The invention relates to drugs comprising modification D of doxazosin mesylate and the use of modification D of doxazosin mesylate for producing drugs for high blood pressure.
Modification D of doxazosin mesylate is prepared by dissolving doxazosin with methanesulfonic acid in methanol, removing any turbidity from the resulting solution, stirring the resulting clear solution until no further precipitate is formed, and removing the precipitate and washing it with methanol and drying it.
To react doxazosin with methanesulfonic acid, the two substances are employed in the molar ratio of about 1:1. It is preferred to use a small molar excess of sulfonic acid (up to about 10%).
If the time between the obtaining of a solution by addition of methanesulfonic acid to the doxazosin and the appearance of a precipitate is insufficient for a filtrationxe2x80x94for example when the reaction is to be carried out on the industrial scalexe2x80x94the time for the filtration can be extended by adding an aprotic polar organic solvent to the methanol used for the reaction.
Examples of aprotic polar organic solvents suitable in this case are N,N-dimethylformamide and, in particular, N-methyl-2-pyrrolidone. The ratio of doxazosin to methanol (weight/volume) or the ratio of doxazosin to methanol to the aprotic polar organic solvent (weight/volume/volume) is about 1: (5 to 15), preferably about 1:(8 to 12) or about 1:(5 to 15) (1.5 to 4), preferably about 1:(8 to 12):(2 to 3).
If in the process the solution obtained after the addition of methanesulfonic acid has to be filtered to remove any foreign particles present, it is preferred to use the solvent mixture comprising aprotic polar organic solvent and methanol. The reason is that in this case, as already mentioned, the time between the obtaining of the solution and the formation of the first crystals is greater than with the use of methanol alone as solvent. If filtration of the solution obtained after the addition of methanesulfonic acid is desired in the process, a particularly preferred procedure comprises using the solvent mixture of aprotic polar organic solvent and, moreover, adding part of the methanol only after the filtration.
Modification D of doxazosin mesylate is characterized in particular by principal lines in the Debye-Scherrer X-ray diffractogram at the following values of 2 theta stated in degrees: 5.72xc2x10.2xc2x0; 11.10xc2x10.2xc2x0; 11.46xc2x10.2xc2x0; 14.14xc2x10.2xc2x0; 17.01xc2x10.2xc2x0; 17.78xc2x10.2xc2x0; 18.33xc2x10.2xc2x0; 20.73xc2x10.2xc2x0; 21.70xc2x10.2xc2x0; 23.12xc2x10.2xc2x0; 24.28xc2x10.2xc2x0; 26.58xc2x10.2xc2x0.
Modification D of doxazosin mesylate has the advantage that it can be processed to tablets more easily. Thus, this modification shows very good miscibility with other substances and an excellent mixing behavior. The very good flow characteristics of the novel modification further facilitate the production of solid pharmaceutical forms.